Inviting controlled chaos into drug synthesis

Asked about recent UNC-Chapel Hill graduate, Pedro de Jesús Cruz, professor of chemistry Jeffrey JohnsonThe initial answer of is a matter of determination.

“Pedro will walk through a brick wall to do something,” Johnson said with a light laugh. “He has an incredibly positive attitude that has served him well in our research projects, and he’s just lovely talking about science with him.”

Pedro de Jesús Cruz holding containers of solid compound produced in the proof of concept study.

More recently, this passion has translated into a proof of concept study Posted in Science which aims to solve a problem that frequently arises in the manufacture of chemical products on a commercial scale: how to create and isolate a desired product without resulting in an abundance of difficult to dispose of by-products.

But getting to this stage of their research required great effort on the part of Jesús Cruz.

“For Pedro’s thesis, he created 500 pages of supporting information on very difficult mechanistic work to better understand the innards of process chemistry,” says Johnson. “It was published in a peer-reviewed journal and also helped us get started with our most recently published study.”

These deep dives are what drew de Jesús Cruz to the field, and ultimately UNC-Chapel Hill, in the first place. But before hitting the waters as a research student, he surfed the coastal waters of his home, Puerto Rico.

“I was very interested in being outdoors as a kid, always skateboarding or surfing. I had no idea what I wanted to do in college, says de Jesús Cruz.

He began his undergraduate studies at the University of Puerto Rico in Cayey as a computer engineering student. Beforehand, he took a course in general chemistry, and his chemical romance began.

“I fell in love. I knew research in chemistry was what I wanted to do, but I didn’t have many opportunities to pursue it where I lived.

His quest led him to the Summer Undergraduate Research Opportunity in Chemistry (SUROC) at UNC-Chapel Hill, where he worked in the lab of Professor Marc Shoenfisch. de Jesús Cruz continued his studies at Carolina with a one-year post-baccalaureate program under the mentorship of Shoenfisch. This eventually led him to apply for graduate school, where he found his calling in organic chemistry.

While studying at Chapel Hill, the first-generation student was also learning English.

“Not only did I have to learn a new area of ​​chemistry, but I basically had to relearn how to talk about it in general because of the differences between the English and Spanish languages,” he recalls.

But he forged ahead, immersing himself in complex issues with the encouragement and support of professors like Johnson, who was the lead author of their most recent proof-of-concept study that re-evaluates purification techniques in chemistry. processes or the large-scale production of chemicals.

Currently, chromatography is commonly used for the purification process, which requires a large amount of solvent – ​​a liquid or gas in which other materials are dissolved – for product purification. This leftover solvent accounts for most of the waste generated in the chemical industry and is neither easy to dispose of safely nor good for the environment.

Pots of solid compound obtained during the Catalyst Recycling scale-up process
Solid compound obtained during the Catalyst Recycling scale-up process.

On a smaller scale, chemists can use a tool for the purification process called crystallization-induced diastereomer transformation (CIDT), which uses minimal amounts of solvents and essentially forces the mixture to purify.

“With CIDT, you produce a mixture of products that have different solubilities, but are also in equilibrium with each other,” Johnson explains. “A product can fall out of solution, leaving other products behind, and mixing will restore its balance. Products that remain in solution continue to transform into what has just fallen out of solution.”

While CIDT in catalytic reactions with a binary mixture – involving two molecular components – has been used in organic chemistry for over 100 years, it has never been proven successful with a quaternary mixture – involving four molecular components. de Jesús Cruz and Johnson did just that. Using what Johnson calls an organic “bread and butter” reaction frequently used in drug development, the research team discovered what they said was hidden in plain sight: a convenient way to cut costs, time and waste by combining creation and purification no.

Jeffrey Johnson, William Cassels, Pedro de Jesús Cruz and Chun-Hsing (Josh) Chen
Jeffrey Johnson, William Cassels, Pedro de Jesús Cruz and Chun-Hsing (Josh) Chen

In fact, proving what these researchers were doing took a lot of time, effort, and resources. This is where the UNC is Basic facilities came into play. In order to provide evidence of the structure of the molecules in their reaction, the research team used the instruments of X-ray diffraction, nuclear magnetic resonance and mass spectrometry in the main laboratories of the department of chemistry. UNC’s central facilities provide access to the equipment that labs like Johnson’s need almost daily.

“When we run the reaction, we have to see what actually happened,” Johnson says. “All the molecules we were working with had exactly the same connections but were arranged differently in space. We use mass spectrometry to see how much a molecule weighs, nuclear magnetic resonance to show what’s connected to what, and X-rays to give a three-dimensional map.

With the bulk of the work of the co-authors William R. Cassels and Chun-Hsing (Josh) Chen, the study lasted about a year and a half. The proof of concept does not guarantee that this method will work for every chemical system and further research is needed, but it has impressive implications. By introducing controlled chaos into process chemistry, large-scale manufacturing processes for industries such as pharmaceuticals and agricultural chemistry could be transformed.

“If you can access more of the compound in a convenient way, we could make the chemistry more sustainable,” says de Jesús Cruz.

Pedro de Jesús Cruz graduated in May from UNC-Chapel Hill with a doctorate in chemistry. He now lives in Pennsylvania and is a discovery chemist at Merck.

Jeffrey Johnson is the A. Ronald Gallant Professor Emeritus in the Department of Chemistry at UNC’s College of Arts and Sciences.

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